CANDIDATE: Stuart A. Scott, Ph.D., is a clinical molecular geneticist in the Mount Sinai Genetic Testing Laboratory, certified by the American Board of Medical Genetics (ABMG), who has drawn on his training and experience in clinical and basic science to develop a research program focused on translational pharmacogenomics. His previous pharmacogenetics research centered on the anticoagulant warfarin and the antiplatelet clopidogrel, and he has co-authored clinical pharmacogenetic practice guidelines for both of these agents. He now seeks a focused four-year K23 Award to support 85% protected time from his clinical responsibilities to initiate a whole-exome sequencing pharmacogenomics research project with related career development as he completes his two-year Institutional KL2 Faculty Scholar award in translational science. CAREER DEVELOPMENT: The long-term goal of the Candidate is to become an independently funded Principal Investigator in the field of translational pharmacogenomics research. This goal will be accomplished through Clinical and Translational Science Award (CTSA)/Pharmacogenomics Research Network (PGRN)- based co-mentorship, collaboration, and the practical and didactic mechanisms outlined in this application. INSTITUTIONAL ENVIRONMENT: The Department of Genetics and Genomic Sciences at the Mount Sinai School of Medicine (MSSM) is a hybrid basic science and clinical department that offers a broad-based program of instruction, research, and clinical services in translational genetics and genomic sciences. The MSSM Institute for Genomics and Multiscale Biology is a central resource for all the equipment and computational support necessary to accomplish modern genomics research. As such, the institutional environment at MSSM is ideal for the proper execution of the studies outlined in this application. RESEARCH PROJECT: Dual antiplatelet therapy (DAPT) with clopidogrel and aspirin is standard of care for patients with acute coronary syndromes (ACS) and/or for those undergoing percutaneous coronary intervention (PCI)~ however, substantial interindividual variability in platelet inhibition and clinical response is commonly observed. Cytochrome P450-2C19 (CYP2C19) is a key enzyme involved in clopidogrel bioactivation and patients who carry CYP2C19 loss-of-function alleles have reduced therapeutic efficacy and increased risks for serious adverse cardiovascular events. However, CYP2C19 only accounts for ~12% of the variability in clopidogrel response. The proposed research project will use whole-exome sequencing and genome-wide genotyping in carefully selected extreme phenotype cohorts of DAPT-treated ACS/PCI patients to identify novel genetic variants, which could facilitate the adoption of genetically guided antiplatelet therapy into routine interventional cardiology practice for more personalized and effective care. The identification of additioal genes and variants will not only influence the uptake of personalized antiplatelet therapy, but could provide a benchmark for other pharmacogenomic studies on drugs and medications with variable responses.
Antiplatelet responses to clopidogrel are highly variable and many patients experience serious adverse events while on treatment. Given that some of the new antiplatelet drugs have contraindications and that clopidogrel recently has come off of patent protection, clopidogrel continues to be very commonly prescribed. Identifying additional important genes and variants involved in clopidogrel response variability beyond CYP2C19 will increase the utility of genetic testing for personalized antiplatelet therapy and could ultimately help guide the implementation of future pharmacogenetic tests for additional drugs with variable responses.
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